Mirtazapine versus megestrol acetate in treatment of anorexia-cachexia in advanced cancer patients: a randomized, double-blind trial

Abstract

Objective

Cancer-related anorexia-cachexia comprises one of the most common syndromes of advanced cancer patients. The management of cancer-related anorexia-cachexia is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of cancer-related anorexia-cachexia. This study is considered to find out whether there is any role of mirtazapine in the improvement of anorexia in cancer patients.

Methods

A total of 80 cancer-anorexia patients were enrolled. Patients in the trial arm received the standard chemotherapy medication plus one tablet of mirtazapine 15 mg daily at night orally for 8 weeks starting from the day of an initial assessment. The control arm received the standard chemotherapy medication plus one tablet of megestrol acetate 160 mg daily orally for 8 weeks starting from the day of an initial assessment. Each patient was assessed by validated versions of Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale v 4 questionnaires.

Results

After 4 and 8 weeks each patient was evaluated again using the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale tool. The quality of life of each patient was assessed by European Organization for Research and Treatment QLQ-C30 v 3.0. After 4 to 8 weeks of treatment, the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale score in cancer anorexia patients in the mirtazapine improved anorexia significantly. However, the improvement after 4 to 8 weeks was not statistically significant when it was compared with the megestrol acetate (P > 0.05).

Conclusions

Therefore, the findings of this study reveal that mirtazapine might be a potential alternative to megestrol acetate, as it has shown potential efficacy as like as megestrol acetate.

anorexia, cachexia, advanced cancer

Introduction

Cancer is a disease in which some of the body’s cells grow uncontrollably and spread to other parts of the body. It can start almost anywhere in the human body, which is made up of trillions of cells. The primary cause of cancer death is widespread metastasis (1). Worldwide in 2020, there were more than 19.3 million new cases of cancer and almost 10.0 million deaths (2). The most common cancers are breast, lung, colon and rectum and prostate cancer (1).

Anorexia (loss of appetite) is a common concomitant of cancer (3). Anorexia may include several symptoms: depression, dysphagia, altered taste perception and nausea. There are numerous causes of anorexia (4). This can be conveniently categorized as being due to central or peripheral mechanisms. In each group, there are also a series of secondary causes due to chemotherapy (5). Changes in serotonin and corticotrophin-releasing factors appear to be the neurotransmitter changes in depression that lead to anorexia (6).

Cancer anorexia is common in specific cancer types: gastric, 85%; pancreatic, 83%; non-small cell lung, 61%; small cell lung, 57%; prostate, 57% and colon, 54%. It involves extreme weight loss and malnutrition (3). Cancer-related anorexia-cachexia (CRAC)’s pathophysiological mechanisms are complex and poorly understood. CRAC may be caused by a chronic, low-grade, tumor-induced activation of the host immune system, which is accompanied by chronic overproduction of cytokines such as interleukin IL-1, IL-6 and tumor necrosis factor (TNF-|$\alpha$|⁠) (7).

Despite the high prevalence of cancer cachexia, few therapeutic options exist and there is no standard of care for its management (8, 9). For this reason CRAC management is a significant challenge in clinical practice. Megestrol acetate (MA) is the most commonly used medication in CRAC treatment at the moment. MA is a steroidal progestin and progesterone derivative that is also known as 17-acetoxy 6-dihydro 6-methylprogesterone. Progestogens, specifically MA, are frequently used to treat anorexia-cachexia. Megestrol’s mechanism of action is thought to involve appetite stimulation via both direct and indirect pathways and antagonism of the metabolic effects of the main catabolic cytokines (10). Mirtazapine, a tetracyclic antidepressant has been described for the management of CRAC based on this fact and is supported by limited evidence from a couple of studies that assessed its impact on appetite in cancer patients. In this study, mirtazapine is considered an effective drug for the treatment of CRAC; those are common for advanced-stage cancer patients.

Mirtazapine is well tolerated and <5% of patients discontinue it because of side effects (11). Mirtazapine is a noradrenergic and specific serotonergic antidepressant that has been used in the management of several symptoms in cancer patients (3). Usually within the first few weeks of treatment. Blockage of postsynaptic 5-HT1b and 5-HT2 receptors with inhibition of release of neuropeptide Y, a brain peptide involved in appetite stimulation; and blockage of the 5-HT3 receptor, which is involved in triggering central nausea. H1 receptor blockade and changes in cytokine levels in the serum.

The purpose of this study was to examine the effectiveness of mirtazapine and MA in the treatment of CRAC in advanced cancer patients.

Methods

Study design and participants

This research was a randomized, double-blind, multicenter trial. The study was conducted on advanced cancer patients with anorexia-cachexia enrolled from the OPD of two hospitals from September 2021 to January 2023. In this study, a total of 80 patients participated with 40 patients in each group, A and B.

Eligible patients were patients at least 18 years of age; had histologically diagnosed advanced-stage tumor at the lung, neck and oral cavity; had assumptive or documented loss of >5% of pre-illness or ideal body weight (body mass index (BMI)) in the previous 3 months and patient Eastern Cooperative Oncology Group (ECOG) performance status 0–3. Eligible patients could begin a new line of chemotherapy within 14 days of randomization be receiving maintenance chemotherapy, or have completed chemotherapy >14 days before randomization with no plan to initiate additional treatment during the study period. Patients with known mechanical obstruction to feeding or uncontrolled diabetes and hypertension were not eligible for study participation. Patients with high doses of corticosteroids and clinically bulky ascites were also excluded. All patients provided written informed consent. The study protocols were approved by the institutional review board or independent ethics committee at each participating center and complied with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice Guidelines and the Declaration of Helsinki.

Sample size

$$ \begin{equation*}n=\frac{P1 (1-P1)+P2 (1-P2)}{(p_1-p_2)^2}\times(Z_{\alpha}+Z_{\beta})^2 \end{equation*} $$

Here,

n = sample size.

Z_α = Z value at a definite level of significance 1.96 at 5% level of significance.

Z_β = Z value at a definite power 0.85 at 80% power.

P₁ = control group response 50% (0.50).

P₂ = treatment group response 20% (0.20).

|$n=\frac{ 0.5(1-0.5) + 0 0.2(1-0.2)}{(0.5-0.2)^2}\times (1.96+0.85)^2$|

|$=\frac{0 .25 \times 0.16}{.09}\times 7.896$|

= 4.5 × 7.89

= 36

In this study, a total of 80 patients participated with 40 patients in each group, A and B. The dropout rate was 10%, which brought down the actual same sample size for each participating group to 36 patients.

Group A—A total of 40 Patients before dropout.

Group B—A total of 40 Patients before dropout.

Outcomes

• The primary outcome was change in improvement of appetite in the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) Anorexia/Cachexia Sub Scale (ACS) score.

• The secondary outcomes were changes in BMI, changes in quality of life (QoL) in the European Organization for Research and Treatment (EORTC) QLQ-C30 score and incidence of treatment-related adverse events.

Statistical analysis

Statistical analysis was done by Microsoft Office Excel 2013. A significant P-value is <0.05.

Patient assessment tools

• FAACT ACS Questionnaire (Bengali v 4)

• EORTC QLQ—C30 (Bengali v 3.0)

• ECOG Performance Status

Study procedure

Before starting the clinical trial, translation and validation of the questionnaire of the FAACT ACS was conducted (12). According to the principle of Consolidated Standards of Reporting Trials (CONSORT), recruitment and enrollment of patients were done. It should be mentioned that medicines were purchased from the manufacturer at the original market price so that there was no conflict of interest. Tablet Mirtazapine (15 mg) and tablet MA (160 mg) were purchased from Incepta Pharmaceuticals Limited, Bangladesh.

Randomization and masking

After determining the sample size, patients were randomly allocated into two arms. Randomization was done by online graph pad software using the computer. The software automatically generated two distinct sets of random numbers after giving the necessary inputs (sample size, sets of numbers). Here every patient had an equal chance to be assigned to any one of the groups (Group A and Group B). Immediately after randomization, random numbers of the two sets were assigned as patient code numbers. One set was designated for Group A, and the other set was for Group B. Then the set of code numbers that belongs to Group A was written as patient ID numbers on the packages containing the mirtazapine tablets. On the other hand, the set belonging to Group B was designated as patient ID numbers on the packages containing MA tablets. This total procedure was conducted by persons unrelated to this research. Thus, the participants and the investigator who require being blind for such a study were effectively blinded from the knowledge about intervention allocation.

Intervention and assessments

Patients diagnosed with CRAC in advanced cancer by a competent clinical oncologist. A total of 80 patients were enrolled after returning informed written consent. Then demographic information, address, mobile number and other information were recorded in a preformed data sheet. Six patients were dropped from the research due to discontinued intervention and death. The dropout cases were excluded from per-protocol analysis. A total of 74 patients were available to complete the study making the per-protocol treatment number 74. The study consisted of three visits, a baseline visit, a follow-up visit at 28 ± 4 days and another follow-up visit at the end of 56 ± 4 days of administration of mirtazapine and MA. At the baseline, the patients were assessed by the translated and validated Bengali version of FAACT ACS. Then patients have given mirtazapine and MA boxes.

Results

Figure 1 shows total of 80 patients were enrolled based on study’s the eligibility criteria. Of which, after decoding, 40 patients were found to receive mirtazapine which was the trial arm, and 40 patients received MA which was the control arm. Six (5) patients dropped out during the research due to discontinued intervention (n = 1) and death (n = 5). Two (12) patients died on the trial arm and three (6) patients died on the control arm. The dropout cases were excluded from per-protocol analysis. At the end of the study, a total of 74 patients were assessed and evaluated.

Figure 1

Flow chart of Consolidated Standards of Reporting Trials (CONSORT).

Figure 2

Scatter diagram showing a linear positive correlation between BMI and FAACT ACS score after 8 weeks of administration of mirtazapine 15 mg tablet daily for 8 weeks along with chemotherapy. Pearson correlation coefficient after 8 weeks was r = 0.34. BMI, body mass index; FAACT, Functional Assessment of Anorexia/Cachexia Therapy; ACS, Anorexia/Cachexia Sub Scale.

Baseline characteristics of patients at the time of enrollment

Table 1 shows the demographic characteristics of patients at baseline. The number of patients in the trial arm was 40 and in control arm was 40. The mean age and SD of patients were 55.52 ± 9.41 in the trial arm and 56.25 ± 12.52 in the control arm and the difference was not statistically significant (P = 0.77). There is a male predominance in both groups. In the trial arm, 17.50%of patients were female, which was 25.00% in the control arm. Whereas 82.50% of patients were male in the trial arm, which was 75.00% in the control arm. The difference was not statistically significant (P = 0.29).

Table 1

Baseline characteristics of patients at the time of enrollment

Variables			Mirtazapine 15 mg n = 40 Mean ± SD	Megestrol 160 mg n = 40 Mean ± SD	P value
Age (years)			55.52 ± 9.41	56.25 ± 12.52	0.77
Gender		Male	33 (82.50%)	30 (75.00%)	0.29
		Female	7 (17.50%)	10 (25.00%)
Site		Oral Cavity	27 (72.97%)	24 (64.86%)	0.49
		Lung	13 (35.13%)	16 (42.24%)
Stage		Stage III	29 (72.50%)	27 (67.50%)	0.62
		Stage IV	11 (27.50%)	13 (32.50%)
BMI			20.49 ± 3.39	19.50 ± 3.32	0.21
ECOG			1.86 ± 0.63	1.86 ± 0.71	1.00

BMI, body mass index; ECOG, Eastern Cooperative Oncology Group.

Figure 3

Scatter diagram showing a linear positive correlation between BMI and FAACT ACS score after 8 weeks of administration of megestrol acetate 160 mg tablet daily for 8 weeks along with chemotherapy. Pearson correlation coefficient after 8 weeks was r = 0.29.

Table 1 shows clinical parameters of patients. In the trial arm, 72.97% of patients had oral cavity cancer and 35.13% had lung cancer. Whereas in the control arm, 64.86% of patients had oral cavity cancer and 42.24% had lung cancer. The difference was statistically insignificant (P = 0.49). In the trial arm, 72.50% of patients had stage III cancer and 27.50% had stage III cancer according to the Tumor Node Metastasis (TNM) staging system. Whereas in the control arm, 67.50% of the patients had stage III cancer and 32.50% had stage IV cancer. The difference was statistically insignificant (P = 0.62).

Comparison of FAACT ACS score of patients between the trail and control arm

Table 2 shows, at baseline the mean score of anorexia in the FAACT ACS scale was 21.68 ± 1.73 in the trial arm compared with 22.43 ± 2.26 in the control arm. The difference between the control and trial arm scores was not statistically significant (P = 0.11).

Table 2

Comparison of FAACT ACS score of patients between the trail and control arm

	Mirtazapine 15 mg n = 37 Mean ± SD	Megestrol 160 mg n = 37 Mean ± SD	P value
At baseline	21.68 ± 1.73	22.43 ± 2.26	0.11
Range, 95% Cl	22.25−21.11	23.16−21.70
After 4 weeks	22.02 ± 2.58	24.08 ± 5.02	0.09
Range, 95% Cl	22.87−21.17	25.73−22.43
After 8 weeks	23.30 ± 4.33	25.30 ± 6.63	0.12
Range, 95% Cl	24.72−21.88	27.51−23.09

FAACT, Functional Assessment of Anorexia/Cachexia Therapy; ACS, Anorexia/Cachexia Sub Scale

After 8 weeks of treatment, anorexia scores were significantly higher both in the trial arm (23.30 ± 4.33; P = 0.03) and control arm (25.30 ± 6.63; P = 0.00) in comparison with score at the end of 4 weeks but at the end of 8 weeks difference between scores of the trial and control arm was not statistically significant (P = 0.12).

Comparison of QoL of cancer patients between the trial and control arm by EORTC QLQ-C30

Table 3 shows, after 8 weeks of treatment, Symptom Assessment scores decreased significantly (P = 0.00) both in the trial and control arm in comparison with baseline. In case of the trial arm the score was 22.91 ± 7.01 and in the control arm score was 26.47 ± 7.90. The difference between scores of the trial and control arm was statistically significant (P = 0.04).

Table 3

Comparison of quality of life of cancer patients between the trial and control arm by EORTC QLQ-C30

EORTC QLQ-C30		Mirtazapine 15 mg n = 37 Mean ± SD	Megestrol 160 mg n = 37 Mean ± SD	P value
Symptom assessment Functional assessment Global assessment	At baseline	43.24 ± 8.08	40.11 ± 7.06	0.08
	Range, 95% Cl	45.91−40.58	42.43−37.79
	After 8 weeks	22.91 ± 7.01	26.47 ± 7.90	0.04
	Range, 95% Cl	25.21−20.61	28.80−24.14
	At baseline	46.72 ± 8.32	50.27 ± 8.41	0.07
	Range, 95% Cl	49.46−43.98	53.04−47.50
	After 8 weeks	61.21 ± 8.24	56.27 ± 9.83	0.02
	Range, 95% Cl	63.92−58.50	60.50−54.04
	At baseline	42.57 ± 11.76	39.86 ± 11.97	0.32
	Range, 95% Cl	46.44−38.71	43.8−35.92
	After 8 weeks	51.02 ± 13.87	44.83 ± 11.53	0.03
	Range, 95% Cl	55.58−46.46	48.62−41.04

EORTC, European Organization for Research and Treatment

Table 3 also shows that after 8 weeks of treatment, Functional Assessment scores increased significantly (P = 0.00) both in the trial and control arm in comparison with baseline. In case of the trial arm the score was 61.21 ± 8.24 and in the control arm score was 56.27 ± 9.83. The difference between scores of the trial and control arm was statistically significant (P = 0.02).

After end of 8 weeks of treatment, Global Assessment scores increased significantly (P = 0.00) in the trial but in control arm score was not significant (P = 0.06) in comparison with baseline. In case of the trial arm the score was 51.02 ± 13.87 and in the control arm score was 44.83 ± 11.53. The difference between scores of the trial and control arm was statistically significant (P = 0.03).

Adverse events during treatment

Table 4 shows the adverse events in the trial and control arms that occurred during the treatment period. There was no significant difference found between adverse events of the trial and control arm after 8 weeks of treatment (P = 0.52). Adverse events of mirtazapine were drowsiness (6), constipation (7) and dry mouth (7), whereas adverse events of MA were constipation (6), nausea (7), dry mouth (12) and edema (7). All the events were mild in form and did not require discontinuation of treatment.

Table 4

Adverse events during treatment

Adverse events	Mirtazapine 15 mg n = 37	Megestrol 160 mg n = 37	P value
Yes	5 (13.51%)	7 (18.52%)	0.52
No	32 (86.49%)	30 (81.48%)

Discussion

There was no significant difference in age, gender, BMI, site of cancer, stage of cancer and duration of anorexia at baseline between mirtazapine and MA.

In this study, oral administration of mirtazapine 15 mg daily at night along with standard chemotherapy medications produces significant improvement of anorexia in advanced cancer patients after 4 to 8 weeks of treatment ( P < 0.05). Mentioned that no significant (P > 0.05) improvement of anorexia is observed up to 4 weeks of treatment. During the comparative study, no significant (P > 0.05) improvement in anorexia after 8 weeks of treatment with mirtazapine is observed with respect to MA, assessed by FAACT ACS scoring system. Mirtazapine appears to be inferior to megestrol in appetite improvement in patients with advanced cancer and ACS (13). In the case of the administration of mirtazapine improvement of anorexia in advanced cancer patients, similar findings are also observed by other researchers (3,11,14). It is assumed that mirtazapine can control the blockage of postsynaptic 5-HT1b and 5-HT2 receptors with inhibition of the release of neuropeptide Y (a brain peptide involved in appetite stimulation), 5-HT3 receptor (which is involved in triggering central nausea) and H1 receptor (blockade and changes in cytokine levels in the serum) after 4 weeks of administration for the advanced cancer patients (15). The present trial observed mirtazapine has a potential efficacy for the treatment of cancer-related anorexia, with 35% of patients gaining at least 1 kg after 8 weeks of therapy. Considering the BMI data for mirtazapine and MA, it is possible to say that no significant (P > 0.05) improvement in BMI for mirtazapine compared with MA after 8 weeks of treatment. In addition, it is also observed that after treatment with mirtazapine, the gaining of weight and appetite is improved to some extent, which is clear from the correlation data (r = 0.35). The finding is consistent with the previous studies Figure 1, 2 (11, 15).

It is known that MA is a good stimulant for appetite and weight gain for advanced cancer patients, which is also observed in this research (P < 0.05). In this regard, the improvement of anorexia in advanced cancer patients is observed from the baseline of the treatment with MA; which is not observed for mirtazapine. Such efficacy of MA is also observed by (16), where a randomized trial has shown that MA significantly improves appetite, resulting in increased food intake and body weight, whereas some trials show no definite improvement in QoL. It is believed that MA has an orexigenic activity and it can increase appetite by controlling calcium channels in the ventromedial hypothalamic satiety center and directly increasing Neuropeptide Y (NPY) levels in the hypothalamus along with it can inhibit the activity of pro-inflammatory cytokines involved in the pathogenesis of cancer anorexia, including IL1, IL6, TNF-|$\alpha$| and IFN-|$\gamma$| (4).

The present study demonstrated a statistically significant difference between mirtazapine and MA in the assessment of the symptom scales (fatigue, insomnia, nausea and vomiting) improvement assessed by EORTC QLQ-C30 v 3.0 questionnaire (P < 0.05).

However, the current study clearly demonstrates that mirtazapine promotes symptom-specific aspects of QoL in advanced cancer patients with anorexia (P < 0.05), as measured by the same instrument, compared with MA.

The current study observed that mirtazapine significantly improves (P < 0.05) global health status/QoL, as measured by the EORTC QLQ-C30 questionnaire but MA cannot show such type of response in global health status/QoL (P > 0.05). Similar results are also found by the EORTC QLQ-C30 instrument, with the use of mirtazapine as compared with MA alone. Multiple placebo-controlled trials have demonstrated that MA does not improve overall QoL in advanced cancer patients with anorexia (17–19).

There was no significant difference (P > 0.05) between the frequency of side effects during mirtazapine and MA treatment. The lack of significant difference is probably due to the small number of patients.

The present study demonstrates that mirtazapine has the potential ability to be an effective drug like MA in improving cancer-related anorexia and QoL. Moreover, it is also a safe drug for the treatment of CRAC. The result of the current study will help CRAC patients, also can help to manage side effects, improve QoL and prevent malnutrition during standard chemotherapy treatment. Therefore, the findings indicate that mirtazapine might be a potential alternative to MA, as it has shown efficacy like MA; and this drug can reduce the expenditure of advanced cancer patients.

Conclusion

It is known that CRAC is related not only with impaired QoL in patients and family members but also with shorter survival. It is also known that the management of CRAC is associated with a great challenge in clinical practice however, for the prevention and treatment of CRAC no definite practice guidelines exist yet. Under this study it is considered to find out whether there is any role of mirtazapine in the improvement of anorexia in cancer patients. After 4 to 8 weeks of treatment with mirtazapine, the FAACT ACS score in cancer anorexia patients in the mirtazapine improved anorexia significantly for a total of 80 patients. To control CRAC among advanced-stage cancer patients, mirtazapine has shown efficacy like MA and the patients will have more treatment options to manage side effects, improve QoL and prevent depression during treatment.

Limitations

First, we did not show improvements in handgrip strength with mirtazapine and MA which was the co-primary endpoint. Second, although our patient-reported measures patients had increased food intake with mirtazapine and MA, we did not measure study participants’ caloric intake or collect food diaries.

Acknowledgments

The authors gratefully acknowledge the contribution of Prof Dr Md. Nizamul Haque, Director, NICRH, Dhaka, Bangladesh.

Conflict of interest statement

None declared.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work is funded by own funding research.

Authors’ contributions

I.C.: Conceptualization, formal analysis, funding acquisition, investigation, methodology, project administration, resources and software, validation, writing original draft, editing and review. N.C.: Conceptualization, funding acquisition, methodology, supervision, validation, writing original draft, editing and review. Y.F.: Conceptualization, methodology, supervision, writing original draft, editing and review. M.T.: Conceptualization, methodology, supervision, writing original draft, editing and review. M.M.: Conceptualization, methodology, supervision, writing original draft, editing and review. N.Z.: Conceptualization, methodology, supervision, writing original draft, editing and review.